This research is focused on the "receptor concept" of cardiovascular infections which afflict several groups of patients (congenital, rheumatic, and degenerative heart disease; open heart surgery; prosthetic valve replacement; vascular grafts and intravascular catheters; and narcotic addicts). Because current experimental and clinical evidence indicates that endothelial injury or replacement of the natural endothelium by prosthetic material promotes development of cardiovascular infections, our emphasis will continue on establishing the nature of the physiologic "barrier" protecting a normally functioning endothelium from microbial agents during episodes of bacteremia. Since the most frequent agents in cardiovascular infections, staphylococci and streptococci, bear specific receptors for "adhesive" plasma proteins (fibrinogen, fibronectin, IgG, Beta2-microglobulin) we will continue our study on the role of these receptors in determining when and how cardiovascular infections are established. We will also examine the role of microbial enzymes in modifying the surface of endothelial cells. We will use bacterial mutants with different pattern of receptors for "adhesive" plasma proteins and we will employ well defined fragments of some of these proteins and synthetic peptide analogs to block the receptor interaction of staphylococci and streptococci in the experimental model of infective endocarditis. We will also study factors modifying the glycocalyx and other surface attributes of endothelial cells in order to define the "host factors" contributing to the attachment of microbial agents and development of thrombotic lesions. They will include platelets, neutrophils, monocytes, endothelial cells and subendothelial zone limited by the basement membrane. Integrating novel methodological approaches to the problem of cardiovascular infections will result in new knowledge concerning microbial receptors, "adhesive" plasma proteins as their ligands, and exposure of andothelial and subendothelial sites whose nature will be defined. This will help us to formulate a new "receptor concept" of cardiovascular infections and to design new approaches to prevent their occurrence and subsequent impairment of heart valves and vascular grafts function.